MiRNA/mRNA Co-profiling Identifies the MiR-200 Family As a Central Regulator of SMC Quiescence

Overview

Journal iScience

Publisher Cell Press

Date 2022 Apr 25

PMID 35465051

Authors

Mingyuan Du

Cristina Espinosa-Diez

Mingjun Liu

Ibrahim Adeola Ahmed

Sidney Mahan

Jianxin Wei

Adam L Handen

Stephen Y Chan

Delphine Gomez

Affiliations

Soon will be listed here.

Abstract

miRNAs are versatile regulators of smooth muscle cell (SMC) fate and behavior in vascular development and disease. Targeted loss-of-function studies have established the relevance of specific miRNAs in controlling SMC differentiation or mediating phenotypic modulation. Our goal was to characterize SMC miRNAome and its contribution to transcriptome changes during phenotypic modulation. Small RNA sequencing revealed that dedifferentiation led to the differential expression of over 50 miRNAs in cultured SMC. miRNA/mRNA comparison predicted that over a third of SMC transcript expression was regulated by differentially expressed miRNAs. Our screen identified the miR-200 cluster as highly downregulated during dedifferentiation. miR-200 maintains SMC quiescence and represses proliferation, migration, and neointima formation, in part by targeting Quaking, a central SMC phenotypic switching mediator. Our study unraveled the substantial contribution of miRNAs in regulating the SMC transcriptome and identified the miR-200 cluster as a pro-quiescence mechanism and a potential inhibitor of vascular restenosis.

Citing Articles

Precision Medicine for Pulmonary Vascular Disease: The Future Is Now (2023 Grover Conference Series).

Forbes L, Bauer N, Bhadra A, Bogaard H, Choudhary G, Goss K Pulm Circ. 2025; 15(1):e70027.

PMID: 39749110 PMC: 11693987. DOI: 10.1002/pul2.70027.

Peripheral Blood miRNA Expression in Patients with Essential Hypertension in the Han Chinese Population in Hefei, China.

Cheng B, Yang R, Xu H, Wang L, Jiang N, Song T Biochem Genet. 2024; .

PMID: 38907084 DOI: 10.1007/s10528-024-10867-6.

Integrative analysis of the lncRNA-miRNA-mRNA interactions in smooth muscle cell phenotypic transitions.

Mahajan A, Hong J, Krukovets I, Shin J, Tkachenko S, Espinosa-Diez C Front Genet. 2024; 15:1356558.

PMID: 38660676 PMC: 11039880. DOI: 10.3389/fgene.2024.1356558.

Role of mechanoregulation in mast cell-mediated immune inflammation of the smooth muscle in the pathophysiology of esophageal motility disorders.

Goyal R, Rattan S Am J Physiol Gastrointest Liver Physiol. 2024; 326(4):G398-G410.

PMID: 38290993 PMC: 11213482. DOI: 10.1152/ajpgi.00258.2023.

Nuclear Control of Vascular Smooth Muscle Cell Plasticity during Vascular Remodeling.

Ahmed I, Liu M, Gomez D Am J Pathol. 2023; 194(4):525-538.

PMID: 37820925 PMC: 10988766. DOI: 10.1016/j.ajpath.2023.09.013.

References

Wang D, Atanasov A . The microRNAs Regulating Vascular Smooth Muscle Cell Proliferation: A Minireview. Int J Mol Sci. 2019; 20(2). PMC: 6359109. DOI: 10.3390/ijms20020324. View

Liu M, Espinosa-Diez C, Mahan S, Du M, Nguyen A, Hahn S . H3K4 di-methylation governs smooth muscle lineage identity and promotes vascular homeostasis by restraining plasticity. Dev Cell. 2021; 56(19):2765-2782.e10. PMC: 8567421. DOI: 10.1016/j.devcel.2021.09.001. View

Park S, Gaur A, Lengyel E, Peter M . The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008; 22(7):894-907. PMC: 2279201. DOI: 10.1101/gad.1640608. View

Clark P, Loher P, Quann K, Brody J, Londin E, Rigoutsos I . Argonaute CLIP-Seq reveals miRNA targetome diversity across tissue types. Sci Rep. 2014; 4:5947. PMC: 4894423. DOI: 10.1038/srep05947. View

Humphries B, Yang C . The microRNA-200 family: small molecules with novel roles in cancer development, progression and therapy. Oncotarget. 2015; 6(9):6472-98. PMC: 4466628. DOI: 10.18632/oncotarget.3052. View

Sun S, Zheng B, Han M, Fang X, Li H, Miao S . miR-146a and Krüppel-like factor 4 form a feedback loop to participate in vascular smooth muscle cell proliferation. EMBO Rep. 2010; 12(1):56-62. PMC: 3024123. DOI: 10.1038/embor.2010.172. View

Shankman L, Gomez D, Cherepanova O, Salmon M, Alencar G, Haskins R . KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med. 2015; 21(6):628-37. PMC: 4552085. DOI: 10.1038/nm.3866. View

Ding J, Zhou S, Guan J . miRFam: an effective automatic miRNA classification method based on n-grams and a multiclass SVM. BMC Bioinformatics. 2011; 12:216. PMC: 3120706. DOI: 10.1186/1471-2105-12-216. View

Zeng Z, Xia L, Fan S, Zheng J, Qin J, Fan X . Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation. Circulation. 2020; 143(4):354-371. DOI: 10.1161/CIRCULATIONAHA.120.049715. View

10.

Nam J, Rissland O, Koppstein D, Abreu-Goodger C, Jan C, Agarwal V . Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell. 2014; 53(6):1031-1043. PMC: 4062300. DOI: 10.1016/j.molcel.2014.02.013. View

11.

Fan P, Chen Z, Tian P, Liu W, Jiao Y, Xue Y . miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival. PLoS One. 2013; 8(4):e60888. PMC: 3630177. DOI: 10.1371/journal.pone.0060888. View

12.

Khorshid M, Hausser J, Zavolan M, van Nimwegen E . A biophysical miRNA-mRNA interaction model infers canonical and noncanonical targets. Nat Methods. 2013; 10(3):253-5. DOI: 10.1038/nmeth.2341. View

13.

Alencar G, Owsiany K, Karnewar S, Sukhavasi K, Mocci G, Nguyen A . Stem Cell Pluripotency Genes Klf4 and Oct4 Regulate Complex SMC Phenotypic Changes Critical in Late-Stage Atherosclerotic Lesion Pathogenesis. Circulation. 2020; 142(21):2045-2059. PMC: 7682794. DOI: 10.1161/CIRCULATIONAHA.120.046672. View

14.

Liao J, Wang J, Liu Y, Li J, Duan L . Transcriptome sequencing of lncRNA, miRNA, mRNA and interaction network constructing in coronary heart disease. BMC Med Genomics. 2019; 12(1):124. PMC: 6708182. DOI: 10.1186/s12920-019-0570-z. View

15.

Farina F, Hall I, Serio S, Zani S, Climent M, Salvarani N . miR-128-3p Is a Novel Regulator of Vascular Smooth Muscle Cell Phenotypic Switch and Vascular Diseases. Circ Res. 2020; 126(12):e120-e135. DOI: 10.1161/CIRCRESAHA.120.316489. View

16.

Sinha M, Ghatak S, Roy S, Sen C . microRNA-200b as a Switch for Inducible Adult Angiogenesis. Antioxid Redox Signal. 2015; 22(14):1257-72. PMC: 4410303. DOI: 10.1089/ars.2014.6065. View

17.

Dobnikar L, Taylor A, Chappell J, Oldach P, Harman J, Oerton E . Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels. Nat Commun. 2018; 9(1):4567. PMC: 6212435. DOI: 10.1038/s41467-018-06891-x. View

18.

Nagao M, Lyu Q, Zhao Q, Wirka R, Bagga J, Nguyen T . Coronary Disease-Associated Gene Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway. Circ Res. 2019; 126(4):517-529. PMC: 7274203. DOI: 10.1161/CIRCRESAHA.119.315968. View

19.

de Rie D, Abugessaisa I, Alam T, Arner E, Arner P, Ashoor H . An integrated expression atlas of miRNAs and their promoters in human and mouse. Nat Biotechnol. 2017; 35(9):872-878. PMC: 5767576. DOI: 10.1038/nbt.3947. View

20.

Choe N, Kwon D, Shin S, Kim Y, Kim Y, Kim J . The microRNA miR-124 inhibits vascular smooth muscle cell proliferation by targeting S100 calcium-binding protein A4 (S100A4). FEBS Lett. 2017; 591(7):1041-1052. DOI: 10.1002/1873-3468.12606. View